This invention relates to methods of treating gastrointestinal hypomotility disorders. In particular, it relates to methods of using a neurotrophin and its analogues enhance gastrointestinal motility.
Constipation, which is the passage of less than 3 bowel movements per week with excessive straining at least 25% of the time, is the most common gastrointestinal complaint in the United States, resulting in about 2 million annual visits to the clinic. (See, National Digestive Diseases Information Clearinghouse) In addition, Americans spend $725 million on laxatives each year without seeking medical help. According to the 1991 National Health Interview Survey, about 4.5 million people in the United States say they are constipated most or all of the time.
Constipation is one of the most common forms of gastrointestinal hypomotility disorders. Constipation also occurs with a number of other conditions including, but not limited to abdominal pain, abdominal cramps, irritable bowel syndrome, non-tropical sprue, megacolon associated with hypothyroidism, pseudo-obstruction of the gastrointestinal tract, colitis, hypomotility of the colon associated with diabetes mellitus, adult onset Hirschsprung""s disease, neurological disorders, myopathic disorders, spinal cord injury, Parkinson""s disease, jejunal-ileal bypass with secondary megacolon, cancer chemotherapy, critical illness including severe burns and other major stresses, with syndromes of depression, the post-operative state, and other pathological conditions.
Gastrointestinal hypomotility disorders also include disorders of the esophagus and gastric-motility including gastric emptying disorders such as diabetic gastroparesis and those that are associated with scleroderma.
Hypomotility may be associated with recurring bouts of hypermotility, the so-called intermittent hypomotility-hypermotility (or irritable bowel) syndrome. Clinical manifestations of this affliction include alternate bouts of constipation and diarrhea, abdominal distention, pains and cramps often relieved by passage of stool. Constipation may also occur in inflammation of gastrointestinal disorders such as ileitis, regional ententes ulcerative and other forms of colitis.
The digestive system functions to process nutrients and other food substances for efficient absorption by the cells of the body. When food is ingested, large particles are broken into smaller particles, enzymes are secreted to decompose food molecules, the products of the digestive action are absorbed, and unused residue is eliminated. In the alimentary canal of the digestive system, food and materials which are by-products of the digestive process are moved along by peristalsisxe2x80x94movement resulting from waves of alternate circular contraction and relaxation of the tubular structure of the canal by which the contents are propelled onward.
In the context of the present invention, motility consists of normal spontaneous coordinated distensions and contractions of the stomach, intestines, colon and rectum to move food through the gastrointestinal tract during the digestive process. Hypomotility disorders are those in which contractions are not occurring naturally or are abnormally slow, resulting in delayed passage of gut contents from stomach to anus. The disorder of unknown cause (idiopathic) in some 50% of the cases (Sleisenger et al., 1989, Gastrointestinal Disease, 4th ed., HBJ, Inc., Philadelphia, pp. 675-713).
Current forms of therapy for such hypomotility syndromes include treatment of the underlying disorder, dietary support, and use of prokinetic agents such as metoclopramide and cisapride (propulsid). In some instances, surgery may be required.
Although metoclopramide is most often prescribed among hypomotility patients, at least one study has indicated that this drug is effective in only 60% of patients with diabetic gastroparesis, and in only 25% of patients with prior gastric surgery (See e.g., Drug Evaluations, 6th ed., AMA, Chicago, 1986, p. 953). In addition, there is evidence that the effectiveness of metoclopramide dissipates with long term use. This appears to be the case at least where diabetes is the underlying disease (Schade et al., 1985, Dig. Dis. Sci., 30:10-15 ). The long term value of the drug has not been established for treating gastric stasis which is either idiopathic or attributed to gastric ulcer.
Another reported disadvantage of metoclopramide therapy is that 20% to 30% of user patients experience side effects including drowsiness, restlessness, anxiety, tremor and muscle rigidity. (see, Sleisenger et al., Id.). In younger patients, metoclopramide frequently causes acute dystonic reactions such as torticollis, trismus, facial spasma, and opisthotonos. Id. In elderly patients, metoclopramide causes Parkinsonian reaction and irreversible tardive dyskinesia. Id. Other side effects of metoclopramide include hyperprolactinemia and subsequent impotence, gynecomastia, amenorrhea, or galactorrhea. Id.
Cisapride is a benzamide and its effects on the motility of the stomach and small bowel closely resemble those of metoclopramide; however, unlike metoclopramide, it also increases colonic motility and can cause diarrhea. (Brunton, 1990, Agents Affecting Gastrointestinal Water Flux and Motility, Digestants, and Bile Acids, in Pharmacological Basis of Therapeutics, Gilman et al., eds., p. 929, Pergamon Press, New York.) The mechanism of cisapride""s gastrointestinal actions is poorly understood. Like metoclopramide, cisapride""s actions are blocked by atropine and may involve the release of myenteric acetylcholine. Id. Cisapride appears to be devoid of dopaminergic blocking activity. Because it lacks central antidopaminergic effects, it does not influence the concentration of prolactin in plasma or cause extrapyramidal symptoms.
However, particularly in combination with other drugs (e.g., antifungals such as ketoconazole, itraconazole, and fluconazole; antibacterials such as erythromycin, clarithromycin, and troleandomycin; and HIV protease inhibitors ritonavir and indinavir), cisapride can cause serious ventricular arrhythmais and sudden death. (1990, New Warnings Added to Cisapride Labeling, JAMA 280:410). The common side effects of cisapride include abdominal cramping, diarrhea, and headache, which lead to drug discontinuation in 2% to 3% of patients.
Thus, there remains a need for improved compositions and methods for treating gastrointestinal hypomobility disorders such as constipation.
The present invention relates to the treatment of gastrointestinal hypomotility, particulary human acute and chronic constipation. More specifically, the invention relates to the use of a neurotrophin for the treatment of gastrointestinal hypomotility.
The invention is based, in part, on the inventor""s discovery that neurotrophin-3 (NT-3) enhances gastrointestinal motility as measured by different parameters. The administration of NT-3 in humans improves stool frequency, colonic motility, gastric emptying and small bowel transit time, with minimal adverse side effects. Both healthy subjects and patients with constipation responded to NT-3 treatment.
One aspect of the present invention provides methods and compositions for the treatment of gastrointestinal hypomotility, typically, chronic constipation, obstipation, idiopathic abdominal distention, irritable bowel syndrome, megacolon associated with hypothyroidism, pseudo-obstruction of the gastrointestinal tract, hypomotility of the stomach and colon associated with diabetes mellitus, neurological disorders, myopathic disorders, spinal cord injury, Parkinson""s disease, geriatric hypomotility disorders, jejunal-ileal bypass with secondary megacolon, hypomotility associated with cancer chemotherapy, hypomotility associated with severe burns and other major stresses, hypomotility associated with syndromes of depression, post-operative intestinal distension, and other pathological conditions, in a subject in need of such treatment. The subject is typically a mammal, and most preferably a human.
In some specific embodiments, NT-3 is used to treat patients experiencing acute constipation associated with orthopedic, gynecological, thoracic, and urological surgery or those experiencing constipation while in a coronary care unit or intensive care unit. In other embodiments, NT-3 is used to treat chronic constipation caused by enteric neuropathy/pseudo-obstruction, Parkinson""s disease, paralysis due to multiple sclerosis, spinal cord injury (resulting in paraplegia or quadriplegia), chronic use of opiate pain killers, irritable bowel syndrome, and constipation in hospitalized/institutionalized patients. NT-3 produced by any method may be used for the practice of the invention; however, recombinant NT-3, such as the recombinant methionyl human NT-3 (r-metNT-3) described in Section 6, infra, is preferred.
In addition to the native NT-3, compositions of chimeras, such as NT-3 fusion polypeptides, peptides or biologically active fragments derived from the NT-3, NT-3 analogues or any other molecules which act as trkB or trkC receptor agonists are useful for the treatment of gastrointestinal hypomotility.
Furthermore, activating antibodies which activate the a NT-3 receptor, such as the trkC receptor, and imitate the effect of NT-3, are also useful for the treatment of gastrointerestinal hypomobility.
Also useful for the treatment of gastrointestinal hypomotility are molecules, preferably small molecules or small peptides, that can activate at any point the signal transduction pathway of NT-3.
In another aspect of the invention, methods and compositions are provided to treat diarrhea or other manifestations of gastrointestinal hypermotility. The subject is typically a mammal, and most preferably a human. Diagnosis of gastrointestinal hypermotility or diarrhea is known by those skilled in the art. The methods of this aspect of the invention comprise administering a therapeutically effective amount of pharmaceutical compositions of a NT-3 receptor antagonist, preferably a trkC receptor antagonist, a neutralizing antibody against a NT-3 receptor, preferably a trkC receptor neutralizing antibody, or a NT-3 neutralizing antibody in an acceptable pharmaceutical carrier, infra, to the subject in need, i.e., a subject afflicted with diarrhea, etc.